Rapidly progressive glomerulonephritis (RPGN) is a kidney syndrome characterized by rapid loss of renal function. If untreated RPGN can result in acute renal failure and death within months. In about 50% of cases, RPGN is associated with an underlying disease, such as Goodpasture syndrome, systemic lupus erythematosus, or granulomatosis with polyangitis; the remaining cases are idiopathic. RPGN encompasses a heterogeneous group of disorders resulting in severe glomerular inflammation and injury. Clinically, RPGN is characterized by a rapid loss of glomerular filtration rate, haematuria, and proteinuria caused by characteristic glomerular lesions such as capillary necrosis and hyperplasia of the parietal epithelial cells (PEC) along Bowman's capsule forming crescents.
The pathogenesis of RPGN involves autoantibodies, immune complex-mediated activation of complement, the local production of cytokines and chemokines and glomerular leukocyte recruitment (Couser, 2012, J Am Soc Nephrol 23:381). RPGN is more common in anti-neutrophil cytoplasmic antibody (ANCA)-associated GN or anti-glomerular basement membrane (GBM) disease than in other forms of GN (Berden et al., 2010, J Am Soc Nephrol 21:1628; Jennette et al., 2006, J Am Soc Nephrol 17:1235). The hallmark of severe GN is glomerular capillary necrosis leading to hematuria and plasma leakage (Bonsib, 1985, Am J Pathol 119:357). PEC exposure to plasma is sufficient to trigger crescent formation (Ryu et al., 2012, J Pathol 228:382) but inflammation and PEC injury serve as additional stimuli (Sicking et al., 2012, J Am Soc Nephrol 23:629). The question of what causes vascular necrosis inside the glomerulus has not previously been answered.
Severe glomerulonephritis involves cell necrosis as well as NETosis, a programmed neutrophil death leading to expulsion of nuclear chromatin leading to neutrophil extracellular traps (NETs). ETosis is a programmed form of cell death of mostly neutrophils (referred to as NETosis) and other granulocytes (Brinkmann et al., 2004, Science 303:1532). NETosis causes an explosion-like directed expulsion of chromatin generating a meshwork called neutrophil extracellular traps (NETs), which immobilize and kill bacteria during infections (Brinkmann et al., 2004, Science 303:1532). Cytokine-induced NETosis also drives sterile injury including necrotizing GN (Kessenbrock et al., 2009, Nat Med 15:623; Kambas et al., 2013, Ann Rheum Dis 73:1854; Nakazawa et al., 2012, Front Immunol 3:333; Tsuboi et al., 2002, J Immunol 169:2026). Many cytosolic or chromatin-related components could account for the toxic and pro-inflammatory effect of NETs, such as proteolytic enzymes or intracellular molecules with immunostimulatory effects, referred to as danger-associated molecular patterns (DAMPs) (Rock et al., 2010, Annual Review of Immunology 28:321).
Histones are nuclear proteins that wind up the double-stranded DNA to form chromatin. Dynamic modifications of histone residues regulate gene transcription by determining the accessibility of transcription factors to their DNA binding sites (Helin & Dhanak, 2013, Nature 502:480). When cell necrosis releases histones into the extracellular space they display significant cytotoxic effects (Hirsch, 1958, J Exp Med 108:925; Xu et al., 2009, Nat Med 15:1318; Chaput & Zychlinsky, 2009, Nat Med 15:1245; Allam et al., 2014, J Mol Med 92:465). Histones contribute to fatal outcomes in murine endotoxinemia caused by microvascular injury and activation of coagulation (Xu et al., 2009, Nat Med 15:1318; Abrams et al., 2013, Am J Respir Crit Care Med 187:160; Saffarzadeh et al., 2012, PLoS One 7:e32366; Semeraro et al., 2011, Blood 118:1952). We previously showed that dying renal cells release extracellular histones that promote septic and post-ischemic acute kidney injury (Allam et al., 2012, J Am Soc Nephrol 23:1375). We further demonstrated that histones act as DAMPs by activating Toll-like receptor (TLR)-2 and -4 as well as NLRP3 (Allam et al., 2012, J Am Soc Nephrol 23:1375; Allam et al., 2013, Eur J Immunol 43:3336), which was confirmed by other groups (Semeraro et al., 2011, Blood 118:1952; Huang et al., 2013, J Immunol 191:2665; Xu et al., 2011, J Immunol 187:2626). TLR2/-4-mediated pathology is an essential mechanism of crescentic GN (Brown et al., 2006, J Immunol 177:1925; Brown et al., 2007, J Am Soc Nephrol 18:1732).
A need exists for improved methods and compositions for treatment of vascular necrosis in severe glomerulonephritis, preferably using histone-neutralizing agents such as anti-histone antibodies or fragments thereof.